Pancreatic ductal adenocarcinoma is a truly devastating disease. Every year, 40,000 Americans are diagnosed with pancreatic cancer; most of them die within one year and less than 5% of those diagnosed with pancreatic cancer have 5 years survival. Alcoholic chronic pancreatitis and smoking are major established risk factors for pancreatic cancer. However, little is known about how they initiate and promote the disease. We hypothesize that alcoholic pancreatitis induces fibrosis leading to apoptosis inhibition; whereas, tobacco smoke inhibits autophagy and apoptosis. These effects when combined with K-ras genetic mutation, which is present in 90% of pancreatic cancer patients, promote pancreatic carcinogenesis. Our preliminary data indicate that Nox4- NADPH oxidase and Akt kinase mediate the carcinogenic effects of alcoholic pancreatitis and smoking. In this project we propose to develop a mouse model of pancreatic cancer that combines alcoholic pancreatitis, smoking exposure, and K-ras genetic mutation. We propose to test the effect of alcoholic pancreatitis and tobacco smoke on the tumorigenesis and survival pathways in pancreas from mice with pancreas-specific K-ras mutation, and in wild type mice. We will complement in vivo results with the in vitro measurements of the effects of smoking on survival pathways and underlying signaling mechanisms in PanIN cells and in pancreatic ductal cells. Finally, we will develop a preventive strategy by using the data of the mechanistic studies. We will apply Nox4 and Akt inhibitors to prevent pancreatic carcinogenesis. The Specific Aims of this proposal are: 1. Determine the effect of alcohol on the pancreatitis-induced fibrosis, survival, and carcinogenesis in wild type and K-ras mutated mice. 2. Determine the effect of tobacco smoke exposure on the pancreatitis-induced fibrosis, survival, and carcinogenesis in wild type and K-ras mutated mice 3. Determine the effect of alcoholic chronic pancreatitis and tobacco smoke combination on fibrosis, survival, and carcinogenesis in wild type and K-ras mutated mice. 4. Determine the effect of NADPH oxidase and Akt inhibitions on preventing the effects of alcoholic chronic pancreatitis and tobacco.